CU-Boulder discovery could lead to new treatments for hepatitis B virus

Study led by Ding Xue pinpoints prime targets of virus in liver cells

A research team led by University of Colorado scientists has discovered two prime targets of the hepatitis B virus in liver cells -- and the findings could be a breakthrough leading to treatment of the disease affecting more than 400 million people worldwide.

For more than three decades, scientists have been trying to find the cellular targets of the hepatitis B virus, said CU professor Ding Xue, who led the study.

Researchers have known that the virus encodes a pathogenic protein -- known as HBx -- allowing tumors to flourish. But how that protein operates has remained largely unknown until now.

"This provides a lot of opportunities for clinical therapeutics to treat hepatitis B," Xue said of the findings from two studies he led that were published Monday.

Although there is a hepatitis vaccine available that has curbed infection rates in the United States, the virus remains a health threat in developing countries, said Xue, of CU's molecular, cellular and developmental biology department.

The World Health Organization estimates 600,000 people die every year from acute or chronic hepatitis B virus infection, which is most predominant in Asia and Africa.

The virus can cause liver inflammation, scarring and cancer. It's transmitted through blood and bodily fluids, unprotected sex, unsterile needles and from an infected mother to her children during birth.

In the two new studies, Xue and his research team showed that the host targets of HBx in human cells are two small proteins, identified as Bcl-2 and Bcl-xL.

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Those cells are known as cell death inhibitors but had not previously been linked to hepatitis B infections. Scientists found that HBx uses a string of amino acids to interact with the Bcl-2 and Bcl-xL targets and set off a spike of calcium in the host cell.

The elevation in calcium triggers viral hepatitis B replication and cell death, Xue said. When the researchers introduced gene mutations in the sequence, HBx binded to the Bcl-2 and Bcl-xL proteins and viral replication was stymied. When those proteins were knocked out or weakened in liver cells, HBx was less able to cause an increase in calcium and viral replication from within the infected cells.

The two papers on the subject were published online in the Proceedings of the National Academy of Sciences. In addition to major CU-Boulder co-authors Xin Geng, Brian Harry, Qinghua Zhou, Yan Qin and Amy Palmer, a group led by professor Ning-Shao Xia from the National Institute of Diagnostics and Vaccine Development in Infectious Diseases at Xiamen University in China collaborated on one of the studies.

Harry said the hepatitis B vaccine, which was developed in 1982, is administered around the world and has been shown to work well in preventing new infections.

"The problem is that once you are infected, there is no effective way to remove the virus from the body," he said in a news release. "When the virus replicates in liver cells, it causes cycles of cellular damage, inflammation and tissue regeneration, resulting in the accumulation of genetic mutations and liver cancer."

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